"In Science the authority embodied in the opinion of thousands is not worth a spark of reason in one man." - Galileo Galilei

Friday, May 7, 2010

Why do you eat grains?

That question isn't is smart-assed as it sounds. Bear with me.

I've blabbed before as to how I've often asked nutrition experts "What's so healthy about 'healthy whole grains'?" I've never gotten an actual answer, and as far as I can tell the best one could say is "nothing in particular." And while I have discussed the possible ways that grain consumption could lead to disease, I would have to admit that the evidence that grains have some particular disease-causing properties (outside of those with obvious clinically-detectable problems, like celiac) seems more correlation than causation at this point.

So I've started rethinking this question more as "why does anybody eat anything?" Clearly the need, at some level, to seek out and consume food has to be innate. And animals evolve amazingly complex behaviors around food. I remember giving my dog an egg for the first time, shell and all. As he does with any food, I expected him to swallow it more or less whole, maybe with a couple of crunches for good measure. Instead, he gently picked it up from his bowl, put it on the ground, and ever-so-delicately cracked it open with his front teeth, then licked out the inside and left the shell. I'm pretty sure that wasn't a learned behavior, unless he's been climbing trees and getting into robins' nests behind my back.

But in general, and probably particularly for omnivores, directed behavior associated with food (like "go find some more of those sweet orange spherical thingies") is learned. Babies put everything in their mouths for a reason: they're figuring out which things are worth seeking out and sticking in their mouths again. You may want to check out this fascinating paper on the topic. The short version is this: there seem to be two main areas of the brain associated with taste. The primary taste cortex handles the innate sensing of taste: sweet, salt, bitter, sour, and umami, along with the texture and viscosity of food (to sense fat), temperature, capsaicin, etc. The response of the primary taste cortex is NOT attentuated by satiety. Something sweet tastes just as sweet whether you're hungry or full. But the primary taste cortex doesn't assign value to a particular taste, i.e. it does not decide whether something tastes "good" or "bad". That's the job of the secondary taste cortex. It is the secondary taste cortex that "decides" sweet things taste good when you're hungry, but no so much after eating a whole box of candy. Secondary taste cortex neurons learn what's good and what isn't, and are further tuned to specific foods. For instance, you can be fed to satiety with fat, and certain neurons will decrease their response to further fat. But the response of those same neurons to the taste of glucose does not decrease, regardless of whether or not you're full of butter. In other words, "there's always room for dessert".

Anyway, let me get to the punch-line from the closing paragraph:

The outputs of the orbitofrontal cortex reach brain regions such as the striatum, cingulate cortex, and dorsolateral prefrontal cortex where behavioural responses to food may be elicited because these structures produce behaviour which makes the orbitofrontal cortex reward neurons fire, as they represent a goal for behaviour. At the same time, outputs from the orbitofrontal cortex and amygdala, in part via the hypothalamus, may provide for appropriate autonomic and endocrine responses to food to be produced, including the release of hormones such as insulin.

In other words, the external response to food (behavior) is a learned response driven by the secondary taste cortex, while the internal response (e.g. hormonal) is innate, originating in the primary taste cortex. That means that you learn what things taste "good" by the secondary taste cortex integrating feedback (positive and negative) from the rest of the body (primary taste cortex, glucose sensors, etc.), reinforcing or weakening the association of that taste with the behavior that led to those stimuli. So the fact that you "like" potato chips is intimately tied up with the impulse to get off the coach at midnight and stumble into the kitchen to finish off the bag. And the only reason you "like" any food is because your brain learned to, associating the flavor with some feedback signals which it interprets as being associated with a net positive outcome.

One other point which is probably obvious, but important: the smaller the time between the flavor stimulus and relevant physiological response, the stronger the change in association with the behavior. Thus, getting cancer 10 years after eating a poisonous plant is not very helpful in weakening that behavior. It is certainly possible to crave something that produces a strong short-term reward, but has a net negative outcome. The brain (both consciously and unconsciously) is notably short-sighted in its assessment of value.

Which brings me back to the original question: why do people eat grains? And I don't mean that as implying there's some moral judgment to made - food morality is just another religion. And there's obviously a spectrum of answers depending on the temporal proximity of the act of eating to a specific endpoint. On end is "prepared properly, they taste good" (I like sourdough toast dripping in butter as much as the next guy, though I eat it rarely). On the other end is the evolutionary argument so brilliantly put forth by Kurt Harris, basically that the net effect of domesticating grains was an advantage in reproductive fitness over hunter-gatherers, regardless of the relative "health" of those doing the reproducing. Evolution cares about making babies, and doesn't care if you have bad teeth and a bum ticker, as long as you contribute genes to more babies than the guy still killing perfectly serviceable beasts of burden with a rock on a stick.

No, I'm interested in the middle area (logarithmically speaking), which is why we learned to like grains. And why do we like them so much that we're willing to go to some amount of trouble to eat them? Why do I so love sourdough toast and butter, even though it doinks my blood sugar and gives me acne?

(Maybe it's the butter - New Zealand makes REALLY good butter.)

I have nothing but vague guesses, and am hoping to get some interesting discussion in the comments.

49 comments:

My son and I are on the SCD, a grain-free diet , which has worked wonders for both of us. Yet so many times I am thought of as wreckless and dangerous. I want to ask these people what is in grains that cannot be found in other foods. Why is a grain-free diet considered so blaphemously dangerous? And when is there going to be a toll-free hotline where folks can call to report my behavior?

Mrs. Ed, I wonder the same thing. I also follow a grain-free diet. I know why *I* do it! I do it because it eliminates the awful GERD symptoms I had, and also eliminates a lot of the aches and pains I thought were all just part of "growing older".

And considering that cultivated grains were not even part of the human diet until about 10,000 years ago, and humankind has been around FAR longer than that, how can *anyone* make a substantiated claim that they are "necessary" for good health?

Taste good? Heck, as Dave said, a slice of sourdough toast dripping with butter tastes great. Chocolate cake with buttercream frosting tastes great too (at least to me who was born with a sweet tooth). But "tastes good" does not equate to "neccessary".

So why did we start to eat grains? Sadly I don't have any fascinating discussion to contribute. I also often wonder who was the first person to consider eating a lobster. LOL

Really Dave, butter without the toast isn't very good either. Its the combination. Grains make lots of things taste good. Cheese and tomato sauce in the case of pizza. Ground beef in the case of burgers (much better with the bun IMO). This is all beside the point. The question is why did we evolve so that these things taste so good? Starch is full of usable energy. I have to think that not getting enough energy was the biggest threat to our hunter-gatherer selves. Anything that provides it will stimulate our pleasure centers. There was never any threat that we'd over-ingest them in such a way as to cause diabetes. None of the food we evolved on was processed. Our bodies can tell that they are full of usable energy but they can't tell that they are causing health problems.

Dave, if there is any desert that I can never fully go without, it's chocolate cake with buttercream frosting (usually in cupcake form for me) -- though I may be getting to the point where I'm satisfied enough with just the buttercream!

If grains do indeed make things taste better, then there should be a biological reason for it. So what biological signal is made more favorable when combining grains with cheese and tomato sauce? Or butter? It's not just the energy density argument, otherwise butter and other pure fat would drive you to eat as much as possible.

Indeed, I know dieters who will happily eat a whole dry toasted bagel - only to eat another one soon after. But does anybody eat 3 tablespoons of straight butter? The butter our family gets is really good - and we often have a bit straight off a spoon. But as tasty as it is, a little goes a long way when taken by itself (that selectivity of the secondary taste cortex strikes again). It's easy to eat 3 tablespoons of butter on a nice piece of toast, though. Why?

I wonder how much of the appeal of grains is the opioids that are present in them. It also seems to me that sugar combined with fat (think frosting) is very easy to over eat compared to just fat by itself or (less so) sugar by itself.

We eat grains for two reasons: one, we have always eaten grains (yes, Neanderthals ate grains, which means the rest of humanity did too), and two, because they're the best source of manganese. Manganese deficiency is the most underappreciated of all deficiencies, and most of us have it.

I'm looking for a deeper biological reason, as discussed in the blog post. "Because we've always done it" is a circular answer. If that's the case, I want to know *why* we've always done it.

Current understanding is that Neanderthals were genetically distinct branch from homo sapiens. Isotopic evidence indicates they were likely top-level carnivores, i.e. did not get significant protein from plant material. See e.g. this paper:

Some brans are very dense in manganese, as are some whole grains (on a per calorie basis). Many other plants are as well, including various greens and wild blueberries. 1000 kcal worth of oats would indeed have about 13 mg of manganese, but also 44 g of protein. The isotopic evidence would seem to rule this out as a significant source of dietary manganese.

There's also the issue of phytates in grains, which tend to block mineral absorption. I don't know the strength of this effect for manganese in particular, but suspect that rather less of it gets absorbed without some sort of "predigestion" technique, like soaking, fermentation, etc.

I'd be interested to know where you got your information about Neanderthal grain consumption, in particular the evidence that they consumed grains, how they prepared them, and relative contribution to caloric intake. Thanks!

I don't have that information, as you will be aware. Neanderthals in the Middle East gathered grain (google 'neanderthal grass panicle'). Did they feed it to their pet mice?

The 'deeper biological reason' for early humans to gather grain is quite simple: nothing stores so well.

Yes, European Neanderthals hunted and ate meat, and their skeletons often have evidence of serious malnutrition. We have all been misled by the term 'top carnivore'.

Phytate is a complete red herring, according to Denis Burkitt. The metals get liberated further down the gut, as long as it isn't too alkaline. Modern high-protein diets make the colon alkaline.

I found out recently that human gut bacteria have phytase. That would make phytate indeed a red herring, and would be another argument for humans being grain-eaters. The best argument of all comes from the Hunza, who ate large quantities of unleavened wholemeal bread and had no degenerative disease at all. See The Wheel Of Health, Wrench 1938.

You don't have which information? I asked a lot of questions - sorry, bad habit.

I'm not saying that Neanderthals (and other hominids) didn't gather and use grains as food (probably along with all kinds of other plant matter). But the isotopic evidence gives greatest weight to the hypothesis that most of their protein came from animal sources. If you have evidence or a hypothesis as to how these isotope ratios can be achieved via a plant-based diet, please post it.

Similarly, Neanderthals had tools clearly used for hunting (unless one thinks they were throwing their spears at grass). Eating grains probably requires some tool use as well, since even the friendliest grain requires some processing to separate the hull, and I think you'd starve to death if you sat around doing it with your fingers. Those tools presumably would have been found along with the hunting tools. What were they?

I have no doubt there are peoples who do reasonably well on grains, suitably processed, possibly supplemented with other sources of micronutrients. There are people who live on unleavened bread who do exhibit severe mineral deficiencies as well. The existence of other factors like this is why observational studies provide limited evidential weight. It's also why I'm asking this question about the biological origins of grain-eating behavior. "Grains store well" is not a behavior, but something that you discover as the result of a behavior. Mice store grain as well, but they didn't just do this spontaneously. Somewhere in the deep past a mouse ancestor got positive biological feedback from eating grains, leading them to ultimately become food. What is that biological feedback in humans?

Your points on phytase are interesting, and I'd love to see some good lab studies on this showing what proportion of the minerals in grain wind up making it into the blood as opposed to coming out the back end.

"According to Denis Burkitt" is evidence of nothing, other than Denis Burkitt talking. One would hope he has stronger evidence to support these statements about phytase, beyond the observational studies that led him to the fiber hypothesis (which, to my knowledge, has yet to gain any climical evidence - feel free to provide such if you know of it).

Your questions were about whether the Neanderthals ATE the grain, how they prepared it, and what proportion of their diet it was. Obviously, I don't have that information. It's difficult enough establishing whether early humans ate any plant food at all.

Yes, I think you're right about the isotope evidence. I have been unable to come up with any other explanation for it with the possible exception of milk.

I don't know how early humans would have de-hulled their grain. I imagine they soaked and sprouted it. Perhaps the hull comes off when you do that, and can be floated away. Do you know if it does?

'There are people who live on unleavened bread who do exhibit severe mineral deficiencies ..'What people do you mean?

'Somewhere in the deep past a mouse ancestor got positive biological feedback from eating grains, leading them to ultimately become food. What is that biological feedback in humans?'Well, obviously animals try out different things, and if something works they try it again. 'Works' means they can digest it and deal with any toxins. I don't see any problem here. If you can catch it and digest it, and it doesn't make you feel sick, you eat it, right?

I thought maybe you knew of other isotopic evidence (grasses sequester carbon differently than leafy plants, and this can be detected in animals that eat grasses, good example in "The Omnivore's Dilemma") or tool discoveries.

I think your point about sprouting is interesting. I wonder if humans actually started eating grains as new grass shoots? Then perhaps worked back to the seeds, particularly once they realized their storage value. It may have been much later, with subsequent tool development, that we figured out the seeds themselves were edible (more or less).

Cordain has a lot of good discussion of mineral deficiencies and grain consumption here:

I didn't go back and read the whole article again, but I think it discusses the higher prevalence of mineral deficiency diseases (e.g. hypogonadal dwarfism) in populations eating unleavened bread, such as rural Iran.

Your last question gets to the heart of the matter. Suppose early humans tried eating some kind of grass. Humans lack the gut mechanisms to digest the grass, so would receive little nutritive value. Let's further suppose the grass didn't cause any obvious illness, so the only feedback would be the sensation of a full stomach, with all other feedback being neutral. Would they have continued eating grass?

I doubt it, since this would be the path to starvation. This is what I was talking about above. The secondary taste cortex integrates various biological feedback to place values on different tastes. High-value foods result in a strong reward stimulus, thus causing the organism to seek out and consume those foods.

Sugar is a great example. The sugar in fruit triggers a rise in insulin, which is detected by the insula (part of the brain). The insula "remembers" the various stimuli (sight, smell, taste, etc.) that led to the insulin signal, because insulin resulting from food generally signals macronutrient density. When presented with similar stimuli again, the insula projects to other parts of the brain to trigger the behavior to get more sugar. Great mechanism when living in the wild, not so much in the modern situation, with essentially unlimited supplies of refined foods.

Part of the reason I asked the original question was because it seems like grains hold a strangely revered place in our culture, indeed across many cultures. As other posters note, people sometimes get severely bent out of shape if you propose that grain might be anything but a boon to health; yet none of these people can come up with a reason why they should be held in such high esteem with regard to nutrition (your point on manganese is the best I've seen). Culture is an emergent property of the behavior of many individuals, and the individual behavior is the result of underlying biology. In other words, I don't think culture happens by accident, or is even driven by our higher mental functions, and strongly suspect the cultural role of grains has its roots in biology.

So what is that biology? I don't know, but I don't think it's just energy or nutrient density. There are plenty of other foods that rank comparably or better in this regard. And I would guess that many of the other aspects of grains that make them "desirable" (e.g. storability, ability to cultivate at high densities) were discovered from the core biological impulse to eat more of them. All guesses, but if you start with the basic premise that behavior is the result of biology, then I find it interesting to try and track down the biology that gives rise to the observed behavior.

Does the insula sense insulin? That's extremely interesting. It means that it senses not just glucose but also magnesium, because insulin promotes magnesium uptake as well as glucose uptake. I've suspected for years that this is how refined carbohydrate makes you fat: you're supposed to stop eating when your brain has enough magnesium.

You need magnesium to make protein, and if you don't have enough you will make fat instead. Your mitochondria also need magnesium, for making ATP, and if they aren't working well you will make fat and not turn over your proteins. Then they get damaged, and you have degenerative disease.

I am really pleased to have that info about the insula, many thanks.

About unleavened wholemeal bread and mineral deficiency. I found out something very interesting about those Iranian teenagers who had short stature and late puberty. Apparently this was a new phenomenon that appeared during the Green Revolution when Iranian farmers tried to grow high-yielding varieties on mineral-poor soil. Their traditional varieties were OK.

In those villages where leavened bread was eaten, no mineral deficiencies were found. In other words, all three factors, mineral-poor soil, unsuitable crop varieties, and unleavened bread were needed to produce this result. And even so, the children weren't really sick, just slow developing.

If this is true, it means that before the Green Revolution, Iranian villagers were eating large quantities of unleavened wholemeal bread, grown on mineral-poor soil, with no ill effects. Quite a revelation.

Dave, I just found this in the British Medical Journal ('Effect of wholemeal and white bread on iron absorption', 17th Sept 1977, p771)

'...The evidence incriminating phytic acid, based on relatively brief studies on humans and animals, is often at variance with epidemiological evidence, the principal exception being the experience in Iran. In South Africa Blacks in rural areas are accustomed to a relatively high intake of phytic acid. Yet our studies on groups on very high intakes compared with those on lower intakes have revealed no differences in mean haematological values, whether in children or adults. Observations on contrasting groups have revealed no differences in mean serum calcium levels, nor in the mean cortical thickness or other dimensions of the second metacarpal. Indeed, we have found satisfactory calcification even in groups of mothers who have had numerous pregnancies and long lactations. Nor in the groups mentioned have we found differences in the growth rate of children. In our appreciation, Third World experience does not support the view that phytic acid is significantly prejudicial to mineral metabolism or to health. ..'

As usual, I can't find the paper I'm thinking of that describes the insula/insulin connection. But here's another one:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC16373/pdf/pq004569.pdf

Note that (according to this paper, at least) that glucose uptake in the brain is NOT regulated by insulin, which is pretty interesting, but maybe not so surprising given the brain's absolute requirement for glucose as a fuel. The brain definitely senses macronutrient concentrations, and though I wouldn't be at all surprised if it also could sense micronutrients like magnesium, I don't know of any specific mechanisms (if anybody does, please post references).

Endogenous opioids may also affect hedonic response in the insula, see

If the opioids in grains are biologically significant, combined with the insulin spike from refined grain foods we might have hedonic double-whammy. Perhaps this is why grains are held in such high esteem. By contrast, sugar only gives you the "glucose/insulin high".

We probably should separate general obesity from metabolic syndrome, for which obesity is one symptom (which not all cases exhibit). I'd bet that magnesium deficiency, along with lots of other deficiencies/excesses in refined foods promote broad-spectrum metabolic imbalance. But I think there's a more direct mechanism by which refined carbohydrates cause overeating, namely the "yo-yo" effect of blood sugar spike, followed by insulin spike, followed by blood sugar crash. The following paper sums this up nicely in Figure 1:

Note that in those eating the high-GI meal, plasma glucose dropped below that of those eating low-GI after about four hours, though insulin was the same at this point. Correspondingly, participants eating the high-GI meal spontaneously consumed more calories in later meals.

It's probably academic at any rate. If you minimize intake of refined carbohydrates in favor of whole foods, you likely avoid the problems, regardless of mechanism.

Pretty interesting stuff on phytic acid. Makes me wonder how much of the current "wisdom" on this topic is just extrapolation from test tube chemistry rather than observations in living organisms. Seems like a pretty easy thing to test directly.

Thanks for the papers. Yes, I found a reference yesterday to insulin action in the insula. Interesting too that opioids are involved. This might be where manganese acts: look up 'mu opioid manganese'.

About magnesium. Magnesium research lags way behind calcium research, and there may be some very interesting things we don't yet know. It was only 5-6 years ago that the magnesium influx channel was identified. It's called TRPM7, and it's regulated in some cells by an enzyme called PI3 kinase. PI3 kinase is activated by insulin, and also by leptin. So far, we don't know whether insulin or leptin activate TRPM7, but we do know insulin promotes magnesium influx. Magnesium might actually be a second messenger like calcium (look up 'magnesium second messenger').

TRPM7 is also permeable to manganese, which might be very interesting indeed. Manganese influx has always been a bit of a mystery.

Magnesium and manganese between them activate practically all the interesting enzymes you can think of, and the yo-yo effect on blood sugar might actually be caused by magnesium/manganese deficiency. If your pancreatic beta cells are deficient, their insulin-producing machinery can't work properly, and they won't respond to a rise in blood glucose fast enough. Glucose will go on rising, and then the beta cells go into panic mode and overshoot.

Magnesium and manganese are also needed in insulin-responsive cells for activation of insulin receptors, so glucose uptake will also be compromised, amplifying the yo-yo.

I'll have to check that stuff out. Your comments are in line with what I've been suspecting about metabolic syndrome, namely that several aspects of modern diets combine for a "perfect storm". I'm guessing major contributors are:* Excess fructose* High-glycemic foods* Mineral deficiencies/imbalance, particularly magnesium* Vitamin D deficiency* Omega-6/omega-3

I wonder the extent to which grains are simply the vehicle to drive these problems, as opposed to having some special disease-causing property?

The worst thing about modern diets is the combination of refined carbohydrate and too much animal food. This diet produces deficiency of copper, manganese and magnesium, and overload of iron, zinc and calcium.

People can't believe this is true, because nutritionists tell us we are actually deficient for iron, zinc and calcium.

Fructose may only be a problem if you have copper deficiency. And low vitamin D is probably a symptom of magnesium/manganese deficiency. The worst thing about vegetable oils might not be the n-3/n-6 ratio but the refining.

My 25 years of reading the biomedical literature full time have led me to the conclusion that whole grains are just about the best things you can eat.

If animal foods are deficient in micronutrients, then presumably the animals we eat are also eating a diet deficient in these micronutrients. And what is fed to most of these animals that we eat? Whole grains.

I think we should be eating cows that eat grass, much as our ancestors have been doing for several hundred thousand years. The irony here is that both humans and cattle have been diverted from their evolutionary diets, and very likely both are suffering as a result.

1. Alzheimer brains have iron and zinc overload, which correlates with pathology.

2. Meat is very high in highly-available iron and zinc.

Need I say more?

Iron overload has been found in many diseases, correlating with pathology. It means manganese deficiency, because only manganese can protect mitochondria from the free radicals produced by excess iron.

Animal products are low in manganese, and refined carbohydrate has had most (grains) or all (sugar) of its manganese removed.

Zinc overload usually means copper deficiency, and much evidence suggests an important role for copper deficiency in Alzheimer's. Utilisation of copper needs manganese, so manganese deficiency might be the primary problem.

Milk is a much better food for humans than meat, but nowadays it's very low in copper. This may be because the cows are fed too much zinc. Nutritionists believe zinc deficiency is common and copper deficiency is rare. But the two top copper researchers, Klevay and Sorenson, both say MOST OF US have copper deficiency. What is often diagnosed as zinc deficiency is actually multiple micronutrient deficiency.

So now you can see why a diet of meat and refined carbohydrate is pretty much guaranteed to give you Alzheimer's. I don't think it helps if the meat is grass-fed, because the basic problem is that meat-derived iron is absorbed without feedback inhibition, and iron doesn't really get excreted. You just accumulate it.

Nutritionists think this is perfectly OK, and they will even give you iron supplements if your 'iron stores' are low. In fact, the iron stores have been shown to be toxic, and we probably shouldn't have any at all.

I think you're mixing up correlation and causation. Alzheimer's brains may be high/low in many things compared to "normal" brains. But you need a biochemical hypothesis connecting iron/zinc overload with the disease outcome. Otherwise you can never tell if it's root cause, a side-effect of some other disease process, or just irrelevant.

And it brings me back to my previous point: if grains are higher manganese, and we're feeding those grains to our meat animals, then why is the meat deficient? The answer may be that we're eating the wrong parts of the animal - hunter-gatherers tended to eschew the muscle for organ meats whenever possible.

And what if you're eating meat WITHOUT refined carbohydrates, which seems closer to the evolutionary diet of humans?

'I think you're mixing up correlation and causation. Alzheimer's brains may be high/low in many things compared to "normal" brains. But you need a biochemical hypothesis connecting iron/zinc overload with the disease outcome.'

I have given you a biochemical hypothesis. Read what I wrote. I can give you as much detail as you like. Ask the questions and I will answer them.

'And what if you're eating meat WITHOUT refined carbohydrates, which seems closer to the evolutionary diet of humans?'

There is a problem here. The human gut does not take kindly to a high-protein diet. Gut bacteria like an acid environment, and protein makes the colon alkaline. This means minerals don't get absorbed properly.

"There is a problem here. The human gut does not take kindly to a high-protein diet. Gut bacteria like an acid environment, and protein makes the colon alkaline. This means minerals don't get absorbed properly."

The relative populations of gut bacteria are dependent on diet. If you move away from a carbohydrate-based diet, the acid-loving bacteria are presumably crowded out by those favoring a more neutral pH. Your comment about "high-protein diet" also brings forth a common misunderstanding. Hunter-gatherers generally did not eat "high protein". Rather the protein content of diets is remarkably constant across cultures. The major source of energy for hunters would have been fat.

I suppose technically you've put forth a "biochemical hypothesis". I'm asking for a few more details linking your hypothetical cause to the disease endpoint, a trip down well-understood metabolic pathways and associated chemistry. The "well-understood" is key, as positing other hypothetical processes does not add any evidential weight (it actually detracts, since your hypothesis space is getting larger). Here's an example I just posted (and admittedly not a great one, but at least some details on how cause is connected to effect):http://sparkofreason.blogspot.com/2010/05/alzheimers-and-rage.html

Still waiting to hear about some whole-grain foods that are not refined carbohydrate.

Thanks for your piece on Abeta and RAGE. It's very interesting, because RAGE has been found to affect the switch between protein synthesis and degradation. Here's a paper about it:http://www.ncbi.nlm.nih.gov/pubmed/19834494

You will be interested to hear that both mTOR and VPS34 have an absolute requirement for manganese. In other words, Abeta and RAGE act as a manganese-dependent switch between protein synthesis and degradation.

RAGE also activates NF-kappaB, which protects mitochondria by inducing manganese-dependent SOD. MnSOD in turn induces many other protective genes, including several involved in autophagy.

Alzheimer's is characterised by failure of autophagy, which is supposed to munch up the damaged proteins.

You might ask, if all this is so well established, why don't Alzheimer researchers talk about it? Very good question. The problem is that biochemists don't think enzyme activation by manganese is physiological. Cells don't have enough manganese.

But actually cells DO have enough manganese. It's just that it's sequestered in membrane-bound compartments. We don't know yet for sure whether it gets released in response to relevant signals, like calcium and magnesium do, but many observations are consistent with this idea. It would mean that locally, the concentration could be very high, high enough to satisfy the biochemists.

So you see, the link between manganese deficiency and Alzheimer's, and all other degenerative diseases for that matter, is up for grabs. And it isn't just degenerative disease. You will be interested to hear that HIV replication is promoted by iron, and inhibited by manganese. The epidemic of AIDS in the third world might conceivably have something to do with the practice of giving pregnant women and children iron supplements.

Hi. Had a busy weekend with the kids. Spent Friday night on a sleep-over aboard the USS Hornet with my son (not much "sleep", unfortunately) and Saturday recovering. Sunday was my daughter's birthday party.

Jane - thanks for all the info you've posted. I haven't had a chance to look in any detail, will respond when/if I have something intelligent to add.

Your info on manganese is pretty interesting, almost sounds like a "forgotten nutrient" to some extent. Hopefully I can get some time to root around through the references you posted.

In general, there seems to be a fairly strong anti-correlation between the degree of refinement of food, and the density of micronutrients. It would be interesting to dig into the causes for this, because it doesn't necessarily HAVE to be this way. Minerals, for example, aren't destroyed by processing, though the relevant biological components might be removed, or chemical alteration may make them less bio-available. It makes me wonder: if grains are high in manganese, and the SAD contains such a high fraction of grain-based foods, what is the origin of manganese deficiency? Is it over-processing? And do you have any evidence that people eating "whole grains" have higher manganese levels and lower rates of (hypothetically) associated diseases?

Re: what whole grain foods are not refined carbohydrate? AFAIK, many grains are not edible raw. Wheat, for instance, will give you quite the stomach-ache (at least it won't kill you outright, like raw kidney beans). This is a great example of how plants (lacking ability to escape or fight) use "chemical warfare". Fruiting plants have evolved to provide an attractive source of nutrition (fruit) to encourage animals to carry away the seeds - indeed, the seeds can survive the digestive tracts. An annual grass, however, packs the seed itself full of nutrition. There is no reproductive benefit to the grass if those seeds are eaten, so from an evolutionary standpoint, it behooves the grass to evolve chemical defenses to discourage predation. Here's a news story with a great example (where the evolution has been helped along by us):

We clever monkeys have figured out how to circumvent at least some of these defenses by "processing" or pre-digesting grains: separating certain components (e.g. removal of the germ takes away some lectins like wheat-germ agglutinin), grinding, fermenting, cooking, etc. All of these processes also affect the availability of nutrients. Many of them free up starch from fiber so that it is more easily assimilated by humans, i.e. raises the glycemic index. Add to this that modern wheat has traded in protein content (40% to 12%) for carbohydrate content, and we can see that modern grain foods certainly have the potential to be very high-glycemic.

So if I'm going to trade in my steak for grains, what grain foods should I be eating that are not highly refined and high glycemic? And while we're on the topic, how should I avoid issues associated with the various chemical defenses of grains? The archeological evidence I'm aware of (admittedly superficial) indicates that all human populations show a decrease in health markers when transitioning from a hunter-gatherer to an agricultural lifestyle. Do you know of any evidence indicating the opposite?

Forget about the defences of grains. Your body can cope with them. IF it has enough vitamins and minerals to activate the enzymes involved. Antinutrients are only toxic to people who eat refined carbohydrate.

Yes, the start of agriculture was accompanied by nutritional problems which have been blamed on grains. Other things happened too, like monoculture and population growth. If you read The Wheel Of Health (about the Hunza) you will see how unlikely it is that these problems were caused by eating grains.

I'm familiar with the basic hypotheses of "The Saccharine Disease", and agree that part of the problem with refined carbohydrates is removal of micronutrients. But increased glycemic load is also a potential issue, driving a hormonal response that (at least on a repeated basis) is closer to the stress response as opposed to a "normal" food response, see e.g. Ludwig's 1999 paper in Pediatrics:

Check out Figure 1, particularly the plasma glucose, epinephrine, and HGH profiles for the high-glycemic meal.

"Forget about the defences of grains. Your body can cope with them. IF it has enough vitamins and minerals to activate the enzymes involved."

That's a pretty broad statement - could you fill in some of the metabolic details connecting the vitamins/minerals and relevant enzymes, how the work to deactivate toxins, etc? "The Wheel of Health" sounds interesting, but I'm only going to take the time to read it if it goes into this level of detail. If it's all associative evidence, I'm not too interested, and suspect you could probably sum it up in a paragraph.

Monocultures and population growth are direct results of adopting large-scale agriculture, and form a feedback loop that is hard to break (monocultures allow you to, at least temporarily, get higher yield per acre, leading to more people, which drives larger monocultures, etc.) It's a classic example of how the strong drive for reproductive fitness can lead to solutions which are optimal in the short-term, but disastrous over the long.

Thanks for the paper. It's very difficult to draw conclusions from it because the subjects were obese, and therefore had micronutrient deficiencies. Several studies have shown that obese people have a low magnesium intake. This means their mitochondria won't be working properly, which indeed is why they are obese. They are making more fat than their mitochondria can burn.

Mitochondria are critically dependent on magnesium. The substrate for ATP synthase isn't ADP, it's magnesium-ADP, and the product is magnesium-ATP. No magnesium, no energy.

These obese subjects won't be able to regulate their blood sugar properly, because their pancreas and liver aren't working optimally. Giving them high versus low glycemic load meals serves only to make the authors think glycemic load is important when it isn't.

Stephan has two excellent posts on glycemic index:http://wholehealthsource.blogspot.com/2009/03/its-time-to-let-go-of-glycemic-index.htmlandhttp://wholehealthsource.blogspot.com/2009/03/more-thoughts-on-glycemic-index.html

My only disagreement with these posts is this: 'I believe wheat is a uniquely unhealthy food, that promotes inflammation and general metabolic havoc over a long period of time.'

This is why I suggested you should read The Wheel Of Health. If you want to know whether wheat really does these things, you have to study people who eat a lot of wheat. The Hunza ate a lot of (unrefined) wheat and were spectacularly healthy.

'..could you fill in some of the metabolic details connecting the vitamins/minerals and relevant enzymes, how they work to deactivate toxins, etc?'

Here is a good discussion of liver detoxification and the vitamins and minerals it needs:http://tuberose.com/Liver_Detoxification.html

Your point about the study subjects being obese is a good one. I've contacted Dr. Ludwig to see if he knows of similar results in non-obese subjects.

"This means their mitochondria won't be working properly, which indeed is why they are obese. They are making more fat than their mitochondria can burn."

Maybe you could explain this in more detail. If they're making more fat, it means they're also eating more glucose. In a properly functioning metabolism, energy intake and expenditure should be balanced. If fat starts stacking up someplace, appetite should be down-regulated. If this does not occur, something else is broken. The sort of hormonal excursions seen in the Ludwig paper are one possible pathway (there are others, but I suspect this one is common in Western society).

I absolutely agree that magnesium is critical for mitochondrial function. But that by itself doesn't imply that magnesium deficiency = obesity, since you still need to explain why other parts of the energy regulation system are not compensating. Indeed, I would expect that magnesium deficiency by itself would result in reduced energy (lethargy) output AND reduced appetite.

I agree with Stephan's comments on glycemic index. When I say "high glycemic", I'm speaking of effect on blood glucose. Ludwig's use of glycemic index is probably reasonable, since the experimental design effectively translates to glycemic load. And of course he was measuring blood glucose directly.

"This is why I suggested you should read The Wheel Of Health. If you want to know whether wheat really does these things, you have to study people who eat a lot of wheat. The Hunza ate a lot of (unrefined) wheat and were spectacularly healthy."

Studying people who eat wheat is a starting point, but ultimately a "black box" approach. It's nearly impossible to factor in all of the variables in lifestyle in metabolism by starting with a particular food in free-living individuals and observing health endpoints. The best you can do is use this as a starting point for testing more detailed metabolic hypotheses.

There is a fair amount of circumstantial evidence that wheat *could* have negative effects on health. For instance, wheat germ agglutinin (WGA) binds to a broad range of hormone receptors. It's so good at this that it is a principle tool used in studying said receptors. WGA binds to and sticks to insulin receptors, which has the *potential* to contribute to metabolic derangement. Nobody has shown that this actually occurs in free-living individuals, but it is at least consistent with what is known at the molecular and cellular level. What I'm trying to elicit from you is similar evidence to the contrary. If "Wheel of Health" goes into that level of detail, I'll read it. If it's all associative, e.g. "These people eat this magic food and they're healthier than you", then I'll pass.

What kinds of grain to the Hunza eat? I was able to find barley, but nothing specific about the wheat strain. And what proportion is grain in their diet? Apparently they also eat a lot of apricots, apricot seed oil, etc. And in what little poking around I did on the internet, the gushing over the "spectacular health" of the Hunza seemed more hyperbolic than based on anything quantifiable. For instance, one site discussed how old men would jump in freezing water. I've seen plenty of old guys with giant beer guts do this as well - it doesn't mean they're "spectacularly healthy".

The info on tuberose.com is interesting, though it seems to be awfully unequivocal in its statements. And if I'm not mistaken, the discussion focuses on fat-soluble toxins. The relevant candidate grain toxins are proteins that make it through the gut into the blood intact. Do you have specific information that the liver neutalizes grain lectins?

'If they're making more fat, it means they're also eating more glucose.' Actually it means their insulin metabolism is deranged. Insulin is supposed to DECREASE fatty acid synthesis in the short term. Here's a quote from a paper entitled 'Insulin acutely decreases hepatic fatty acid synthase activity':

'Chronically elevated levels of insulin increase the levels in liver of lipogenic enzymes .. Growing evidence supports a central role for de novo synthesis of fatty acids (FA) and increased hepatic VLDL-triglyceride output in the pathogenesis of obesity and insulin resistance.'http://www.ncbi.nlm.nih.gov/pubmed/16054098

You need periodic absence of insulin for it to work properly. Insulin secretion is supposed to be pulsatile. Oscillations of insulin secretion depend on oscillations in mitochondrial ATP synthesis, and therefore on magnesium. Many studies have shown an inverse relation between serum magnesium and insulin resistance.

'The relevant candidate grain toxins are proteins that make it through the gut into the blood intact.'

Many proteins get through the gut wall intact, it's part of 'oral tolerance' in which the immune system is instructed not to react to them.

Grain proteins are only toxic if they aren't accompanied by the vitamins and minerals needed for proper functioning of the gut and the immune system. Gut cells and immune cells both use glutamine as an energy source, and much of it is made by the enzyme glutamine synthetase. This enzyme is activated by magnesium and manganese.

Gut cells sit on a basement membrane which has to be repaired all the time, just like the basement membrane of blood vessels has to be repaired all the time. Repair needs the copper enzyme lysyl oxidase, which is why copper-deficient animals get ruptured blood vessels.

Celiac patients have holes in their gut basement membrane, and this might be the main route through which gluten gets inside. Blame copper deficiency, not the gluten.

I should have said "storing more fat" rather than making more fat. Storage of fat requires glucose as a source of glycerol-3-phosphate. And I agree with your comments on deranged insulin metabolism. A great way to drive said derangement is by spiking blood glucose with refined carbohydrates, like nearly all grain-based foods. Do you have any examples of grain-based foods for which the blood sugar and insulin responses are on a par with whole food sources of carbohydrate?

"Grain proteins are only toxic if they aren't accompanied by the vitamins and minerals needed for proper functioning of the gut and the immune system. Gut cells and immune cells both use glutamine as an energy source, and much of it is made by the enzyme glutamine synthetase. This enzyme is activated by magnesium and manganese."

Interesting hypothesis, but your case is circumstantial. Do you have specific evidence relating glutamine metabolism and lectin detoxification? It's a bit academic, I know, since we don't really have any direct evidence that grain lectins play a causal role in disease.

"Celiac patients have holes in their gut basement membrane, and this might be the main route through which gluten gets inside. Blame copper deficiency, not the gluten"

Here is a list of foods ranked by copper content per 200 kcal serving:

Note that grains first appear quite far down the list. At the top: mollusks and organ meats. Considerable evidence exists and continues to mount that these were staples in early human diets, not grains. I would suggest that the fast track to copper deficiency is getting a large proportion of calories from grains. And for all minerals under discussion, I've yet to see any real evidence that phytates don't interfere with mineral bioavailability.

Some differences here, because some of the foods with high magnesium/kcal density are of low caloric density. For instance, you'd need to eat more than a kilogram of raw chard to get 200 kcal. Many examples here of seeds and nuts that would have been on the paleolithic menu. Grain brans are notably high, but of course you'd need the technology to separate the bran, and I'd further question bioavailability. I'd love to see some controlled studies where they feed subjects rice bran, and see how much magnesium comes out the back end. It's unfortunate that we don't have some solid info on magnesium in pastured animals vs. grain fed, though what results I've seen indicate that it is higher (as you'd expect for animals eating leaves instead of grains).

This is really the one micronutrient where whole grains make much of a showing. We also have lots of seeds and nuts again, also shellfish and some fruits (like wild blueberries).

So once again we return to my original question: grains are not impressive in terms of micronutrient density (excepting manganese), particularly if you take extensive processing and refinement out of the equation. So what is the biological imperative to eat them? We find in the lists above plenty of alternative foods which are both generally more dense in micronutrients as well as easier to harvest and make edible with limited technology.

'I would suggest that the fast track to copper deficiency is getting a large proportion of calories from grains. And for all minerals under discussion, I've yet to see any real evidence that phytates don't interfere with mineral bioavailability.'

Look up 'Enhancement of Cu bioavailability in the rat by phytic acid'. The authors suggest phytate improves copper availability by binding zinc, which would otherwise inhibit copper absorption.

In fact Klevay suggested years ago that the problem in heart disease was a high zinc-copper ratio, and that phytate reduces it.

As far as I have been able to find out, phytate binds zinc, iron and calcium better than copper, manganese and magnesium, and therefore has the potential to correct all the imbalances caused by overconsumption of animal foods.

"As far as I have been able to find out, phytate binds zinc, iron and calcium better than copper, manganese and magnesium, and therefore has the potential to correct all the imbalances caused by overconsumption of animal foods."

You're weaving quite the web of ad hoc hypotheses. What you've put forth above would seem to contradict your stance that coeliac is the result of copper deficiency. If eating lots of grains corrected mineral balance as you claim, then more grains should improve coeliac, not less. And didn't you say that gut bacteria neutralized phytate? Or are you saying that one should only eat a lot of grains IF also eating a lot of animal-based foods?

Is it your stance that "imbalances caused by overconsumption of animal foods" are intrinsic to consuming animal foods, or a result of how we raise and eat animals today? For instance, we feed cattle grain, and eat only the muscle meat, which has a relative paucity of micronutrients compared to organ meats. Because it would seem strange if you are claiming that humans somehow evolved such that a major component of their diet was less than optimal.

And again, what grain-based foods do not have a large effect on blood glucose and insulin (compared to whole foods like steak and veggies)?

Here's a thought from a non scientist...As soon as the lands rose up from the oceans and the volcanos quieted, the earth began to lose its balance of minerals back to the seas. Life on earth also began to be affected by such loss. Perhaps (as is often the case) animals were able to adapt to that loss more quickly evolutionarily speaking, than humans.

Humans are lacking in the balance of the 92 odd minerals in ways which science does not yet nearly understand. (And 'balance' is the operative word).

Over time and with prolonged lack, will not the body seek to redress this apparent 'starvation' by a 'hunger' for the quick fix and storability (in the body) of carbs/grains/sugars?IMHO, we need to intervene at a much lower level, viz a complete mineral cocktail. Otherwise we just go round in circles trying to second guess the body in all its infinite complexity.

We need to learn to take from the source and put back on the land. Some.. such as Rene Quinton in France at the turn of the century, understood this. I believe somewhere in Canada (and with a UK offshoot, and probably USA too) there is an agro company that also understands this. I'm sure in some of the 'unknown' corners of the world there are folk who have been doing this for generations in their own small way on their own small patches.

Personally I know how I am affected by eating grains and A1 milk and also high salicylate foods. (I'm hoping this is temporary but am prepared for it not to be). No matter what the so called experts tell us we have to go with our guts.